Depression is the most common neuropsychiatric manifestation following stroke. Depression amongst U.S. Veteran stroke survivors occurs more frequently than in non-Veterans and is associated with increased health care utilization, including more frequent and lengthier hospitalizations. Post-stroke depression (PSD) also interferes with functional recovery. The neuroplastic processes underlying stroke rehabilitation are likely impeded by depression thus limiting the response to rehabilitative strategies. However, little is known about the neurobiological mechanisms underlying PSD in Veterans. Thus, the overarching aim of this proposal is to examine the neurobiological underpinnings of PSD. Non-stroke, depressed cohorts have demonstrated that reduced neuroplastic potential, and brain-derived neurotrophic factor (BDNF) are potential candidate mechanisms underlying PSD. Additionally, mechanisms appear to be restored with successful antidepressant treatment. Given that pharmacologic treatments for depression are often ineffective and come at the cost of significant side effects, alternative treatments for Veterans with PSD are needed. Aerobic exercise (AEx) is an attractive treatment option given its robust health benefits, established anti-depressant benefits, and ability to modulate neuroplastic potential and BDNF. Therefore, an additional aim of this project is to examine the acute effects of AEx on neuroplastic potential and BDNF in PSD. Identifying the neurobiological underpinnings of PSD may help providers identify candidates for early evidence-based anti-depressant treatments as well as educate Veterans and their families about the nature of this condition. Additionally, establishing the acute influence of AEx on these biomarkers of neuroplasticity will aide in the development of optimal treatment strategies. The aims of this study will be accomplished by examining a cohort of stroke survivors with and without PSD who will undergo a non-invasive brain stimulation assessment of neuroplastic potential called paired associative stimulation (PAS). Additionally, we will assess the influence of three distinct exercise conditions, high-intensity AEx (HI); low-intensity-AEx (LO); or a non-exercising control (CON) on neuroplastic potential and circulating BDNF. This proposal will be supported by the infrastructure and resources provided by the South Carolina Research Center for Recovery from Stroke (NIH P20 GM109040). Furthermore, the combination of the Ralph H. Johnson VA Medical Center and its affiliated academic institution, Medical University of South Carolina is uniquely positioned to fill the aforementioned gap in understanding for several reasons: 1) Charleston, South Carolina has one of the highest rates of stroke in the nation, and 2) in the last 3 years we have received over $23 million in research funds to support rehabilitation research in stroke recovery. During the award period, the applicant will capitalize on the opportunity to utilize these resources to develop the requisite skills and understanding of neurobiological data acquisition, analysis, and interpretation through direct hands-on training from local renowned experts. The overall goal of this Career Development Award application is to expose the candidate to the rich local environment for stroke recovery research so as to provide the foundation for his development into an independent VA researcher studying the effects of activity-based interventions, alone or as adjuvants, for the treatment of PSD. To accomplish this goal, the proposed training plan will enhance the candidate?s understanding of both the neurobiological underpinnings as well as the clinical manifestations of PSD through further training in the acquisition, analysis, and interpretation of neurobiological and clinical assessment of stroke and depression. The data generated from this proposal will inform clinicians, patients, and caregivers on the neurobiological basis of PSD and facilitate informed decisions on treatment options. A neurobiological model of PSD will provide the scientific community with a framework to support the innovation of neurobiologically- specific therapies and ultimately lead to novel treatments for PSD.